The rapid infusion of citrate anticoagulant during large volume leukapheresis (LVL) results in acute decreases in serum concentrations of the physiologically active (ionized) form of calcium and magnesium leading to citrate toxicity. Prophylactic intravenous (IV) calcium supplementation during these procedures has been shown to avert the most serious symptoms of citrate toxicity. However, role of magnesium supplementation was not investigated. We studied the effect of prophylactic IV magnesium supplementation on metabolic parameters and citrate-related symptoms. Normal healthy allogeneic donors (n=30) were enrolled in the randomized, placebo-controlled study (placebo=16, IV magnesium=14). All donors received prophylactic IV calcium. Each donor underwent up to three LVL procedures. Magnesium administration lessened the degree of ionized hypomagnesemia and hypocalcemia, and facilitated a longer lasting response of parathyroid gland to decreased serum ionized calcium. In addition, the progressive decreases in serum ionized magnesium concentration seen after repeat LVL procedures in the placebo group were attenuated by magnesium administration. However, magnesium administration did not improve the residual citrate related symptoms and, based on this study, prophylactic administration of magnesium should be considered only in donors with prior hypomagnesemia or during consecutive LVL procedures.